title: Sensitization of pancreatic cancer to chemoradiation by the Chk1 inhibitor MK8776.
abstract: OBJECTIVE
  The combination of radiation with chemotherapy is the most effective therapy for unresectable pancreatic cancer. To improve upon this regimen, we combined the selective Checkpoint kinase 1 (Chk1) inhibitor MK8776 with gemcitabine-based chemoradiation in preclinical pancreatic cancer models.
  
  
  METHODS
  We tested the ability of MK8776 to sensitize to gemcitabine-radiation in homologous recombination repair (HRR)-proficient and -deficient pancreatic cancer cells and assessed Rad51 focus formation. In vivo, we investigated the efficacy, tumor cell selectivity, and pharmacodynamic biomarkers of sensitization by MK8776.
  
  
  RESULTS
  We found that MK8776 significantly sensitized HRR-proficient (AsPC-1, MiaPaCa-2, BxPC-3) but not -deficient (Capan-1) pancreatic cancer cells to gemcitabine-radiation and inhibited Rad51 focus formation in HRR-proficient cells. In vivo, MiaPaCa-2 xenografts were significantly sensitized to gemcitabine-radiation by MK8776 without significant weight loss or observable toxicity in the small intestine, the dose-limiting organ for chemoradiation therapy in pancreatic cancer. We also assessed pChk1 (S345), a pharmacodynamic biomarker of DNA damage in response to Chk1 inhibition in both tumor and small intestine and found that MK8776 combined with gemcitabine or gemcitabine-radiation produced a significantly greater increase in pChk1 (S345) in tumor relative to small intestine, suggesting greater DNA damage in tumor than in normal tissue. Furthermore, we demonstrated the utility of an ex vivo platform for assessment of pharmacodynamic biomarkers of Chk1 inhibition in pancreatic cancer.
  
  
  CONCLUSIONS
  Together, our results suggest that MK8776 selectively sensitizes HRR-proficient pancreatic cancer cells and xenografts to gemcitabine-radiation and support the clinical investigation of MK8776 in combination with gemcitabine-radiation in locally advanced pancreatic cancer.
authors.affiliation: Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, Michigan 48109-5637, USA.
authors.forename: Carl G
authors.initials: CG
authors.lastname: Engelke
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Parsels
authors.forename: Yushen
authors.initials: Y
authors.lastname: Qian
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.forename: David
authors.initials: D
authors.lastname: Karnak
authors.forename: Jordan R
authors.initials: JR
authors.lastname: Robertson
authors.forename: Daria M
authors.initials: DM
authors.lastname: Tanska
authors.forename: Dongping
authors.initials: D
authors.lastname: Wei
authors.forename: Mary A
authors.initials: MA
authors.lastname: Davis
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Parsels
authors.forename: Lili
authors.initials: L
authors.lastname: Zhao
authors.forename: Joel K
authors.initials: JK
authors.lastname: Greenson
authors.forename: Theodore S
authors.initials: TS
authors.lastname: Lawrence
authors.forename: Jonathan
authors.initials: J
authors.lastname: Maybaum
authors.forename: Meredith A
authors.initials: MA
authors.lastname: Morgan
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D059248:Chemoradiotherapy; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D059767:Recombinational DNA Repair / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: C559815:MK-8776; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D011838:Radiation-Sensitizing Agents; D003841:Deoxycytidine; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; D000093542:Gemcitabine